Solid state forms of trisodium valsartan: sacubitril

ABSTRACT

Solid state forms of trisodium valsartan:sacubitril, processes for their preparation, pharmaceutical compositions containing such solid state forms and treatment methods using the pharmaceutical compositions are described.

This application is a continuation application of U.S. patentapplication Ser. No. 15/735,717, which is a National Stage applicationof PCT/US2016/036905, filed 10 Jun. 2016, which is related to, andclaims the benefit of priority of, U.S. Provisional Application No.62/174,938 filed on 12 Jun. 2015, U.S. Provisional Application No.62/212,817 filed on 1 Sep. 2015, and U.S. Provisional Application No.62/311,070 filed on 21 Mar. 2016, all of which are entitled SOLID STATEFORMS OF TRISODIUM VALSARTAN:SACUBITRIL, the contents of which areincorporated herein by reference in their entirety for all purposes.

FIELD OF THE INVENTION

The present invention encompasses solid state form of trisodiumvalsartan:sacubitril and processes for its preparation

BACKGROUND OF THE INVENTION

Valsartan:sacubitril (codenamed LCZ696) is a combination drug consistingof two antihypertensive (blood pressure lowering drugs), valsartan andsacubitril.

The combination is often described as a dual-acting compounds ofangiotensin receptor blockers (ARB) and neutral endopeptidase inhibitors(NEPi). Valsartan is described in U.S. Pat. No. 5,399,578 and Sacubitrilin U.S. Pat. No. 5,217,996. U.S. Pat. No. 8,877,938 describes complex oftrisodium valsartan-sacubitril hemipentahydrate in crystalline form.

Polymorphism, the occurrence of different crystalline forms, is aproperty of some molecules and molecular complexes. A single moleculemay give rise to a variety of polymorphs having distinct crystalstructures and physical properties like melting point, thermal behaviors(e.g. measured by thermogravimetric analysis—“TGA”, or differentialscanning calorimetry—“DSC”), X-ray diffraction pattern, infraredabsorption fingerprint, and solid state (¹³C-) NMR spectrum. One or moreof these techniques may be used to distinguish different polymorphicforms of a compound.

Different salts and solid state forms (including solvated forms) of anactive pharmaceutical ingredient may possess different properties. Suchvariations in the properties of different salts and solid state formsand solvates may provide a basis for improving formulation, for example,by facilitating better processing or handling characteristics, changingthe dissolution profile in a favorable direction, or improving stability(polymorph as well as chemical stability) and shelf-life. Thesevariations in the properties of different salts and solid state formsmay also offer improvements to the final dosage form, for instance, ifthey serve to improve bioavailability. Different salts and solid stateforms and solvates of an active pharmaceutical ingredient may also giverise to a variety of polymorphs or crystalline forms, which may in turnprovide additional opportunities to assess variations in the propertiesand characteristics of a solid active pharmaceutical ingredient.

Discovering new salts, solid state forms and solvates of apharmaceutical product may yield materials having desirable processingproperties, such as ease of handling, ease of processing, storagestability, and ease of purification or as desirable intermediate crystalforms that facilitate conversion to other polymorphic forms. New solidstate forms of a pharmaceutically useful compound can also provide anopportunity to improve the performance characteristics of apharmaceutical product. It enlarges the repertoire of materials that aformulation scientist has available for formulation optimization, forexample by providing a product with different properties, e.g., adifferent crystal habit, higher crystallinity or polymorphic stabilitywhich may offer better processing or handling characteristics, improveddissolution profile, or improved shelf-life (chemical/physicalstability). For at least these reasons, there is a need for additionalsalts and solid state forms (including solvated forms) of trisodiumvalsartan:sacubitril.

SUMMARY OF THE INVENTION

The present invention provides a solid state form of trisodiumvalsartan:sacubitril referred hereto as form II and pharmaceuticalcompositions thereof.

The present invention also encompasses a process for preparing the abovesolid state form.

The present invention provides a solid state form of trisodiumvalsartan:sacubitril for use in the preparation of pharmaceuticalcompositions and/or formulations of this compound.

The present invention also encompasses the use of the solid state formof trisodium valsartan:sacubitril of the present invention for thepreparation of pharmaceutical compositions and/or formulations of thiscompound.

The present invention comprises a process for preparing the abovementioned pharmaceutical compositions. The process comprises combiningthe trisodium valsartan:sacubitril with at least one pharmaceuticallyacceptable excipient.

The trisodium valsartan:sacubitril form, and the pharmaceuticalcompositions and/or formulations of the present invention can be used asmedicaments, particularly for the treatment of hypertension and heartfailure.

The present invention further provides trisodium valsartan:sacubitrilfor use in the preparation of other solid state forms ofvalsartan:sacubitril.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows an X-ray powder diffractogram of trisodiumvalsartan:sacubitril form II.

FIG. 2 shows DSC thermogram of trisodium valsartan:sacubitril form II.

FIG. 3 shows an X-ray powder diffractogram of amorphous trisodiumvalsartan:sacubitril.

FIG. 4 shows DSC thermogram of amorphous trisodium valsartan:sacubitril.

FIG. 5 shows ¹³C NMR spectrum of trisodium valsartan:sacubitril form II.

FIG. 6 shows FTIR spectrum of trisodium valsartan:sacubitril form II.

FIG. 7 shows SEM images of spherical particles of trisodiumvalsartan:sacubitril form II.

FIG. 8 shows an X-ray powder diffractogram of sacubitril sodium salt.

FIG. 9 shows an X-ray powder diffractogram of valsartan disodium salt.

FIG. 10: Full peak list of trisodium valsartan:sacubitril form II (Table1).

FIG. 11: Peak list of form II (two theta values) and correspondingd-spacing values as calculated by HighScore software (Table 2).

FIG. 12 shows an X-ray powder diffractogram of LCZ696 withcharacteristic peaks at 4.2, 5.0, 6.5 and 12.6 degrees 2-theta±0.2degrees 2-theta.

FIG. 13: TGA thermogram of trisodium valsartan:sacubitril form II.

FIG. 14: X-ray powder diffractogram crystalline trisodiumvalsartan:sacubitril form II prepared according to Example 18.

DETAILED DESCRIPTION OF THE INVENTION

The present invention encompasses solid state form of trisodiumvalsartan:sacubitril. Solid state properties of trisodiumvalsartan:sacubitril can be influenced by controlling the conditionsunder which the trisodium valsartan:sacubitril is obtained in solidform.

As used herein, valsartan:sacubitril (valsartan:sacubitril cocrystal)also refers to trisodium valsartan:sacubitril cocrystal in hydrate form(also known as LCZ696).

In some embodiments, the solid state form of trisodiumvalsartan:sacubitril of the invention is substantially free of any otherforms of trisodium valsartan:sacubitril.

As used herein, “substantially free” is meant that the solid state formof the present invention contains 20% (w/w) or less of polymorphs, or ofa specified polymorph of trisodium valsartan:sacubitril. According tosome embodiments, the solid state form of the present invention contains10% (w/w) or less; or 5% (w/w) or less; or 2% (w/w) or less ofpolymorphs, or of a specified polymorph of trisodiumvalsartan:sacubitril. In other embodiments, the solid state form oftrisodium valsartan:sacubitril of the present invention contains from 2%to 20% (w/w); or from 5% to 20% (w/w); or from 5% to 10% (w/w) of one ormore solid state forms or one or more polymorphs of trisodiumvalsartan:sacubitril which is/are different from the predominant solidstate of trisodium valsartan:sacubitril which is present.

Depending on which other solid state forms comparison is made with, thecrystalline form of trisodium valsartan:sacubitril of the presentinvention has advantageous properties selected from at least one of thefollowing: chemical purity, flowability, solubility, dissolution rate,morphology or crystal habit, stability—such as chemical stability aswell as thermal and mechanical stability with respect to polymorphicconversion, stability towards dehydration and/or storage stability, lowcontent of residual solvent, a lower degree of hygroscopicity,flowability, and advantageous processing and handling characteristicssuch as compressibility, and bulk density. Particularly, the crystallineform of trisodiuim valsartan:sacubitril of the present invention hasgood flow and compression properties, which are particularly useful forprocessing and handling, for example during filtration and formulationprocesses. In some embodiments, the present invention providescrystalline form of trisodium valsartan:sacubitril having advantageousmorphology, in particular uniform morphology.

A solid state form, such as a crystal form or amorphous form, may bereferred to herein as being characterized by graphical data “as depictedin” or “as substantially depicted in” a Figure. Such data include, forexample, powder X-ray diffractograms and solid state NMR spectra. As iswell-known in the art, the graphical data potentially providesadditional technical information to further define the respective solidstate form (a so-called “fingerprint”) which cannot necessarily bedescribed by reference to numerical values or peak positions alone. Inany event, the skilled person will understand that such graphicalrepresentations of data may be subject to small variations, e.g., inpeak relative intensities and peak positions due to certain factors suchas, but not limited to, variations in instrument response and variationsin sample concentration and purity, which are well known to the skilledperson. Nonetheless, the skilled person would readily be capable ofcomparing the graphical data in the Figures herein with graphical datagenerated for an unknown crystal form and confirm whether the two setsof graphical data are characterizing the same crystal form or twodifferent crystal forms. A crystal form of a trisodiumvalsartan:sacubitril referred to herein as being characterized bygraphical data “as depicted in” or “as substantially depicted in” aFigure will thus be understood to include any crystal forms of trisodiumvalsartan:sacubitril characterized with the graphical data having suchsmall variations, as are well known to the skilled person, in comparisonwith the Figure.

As used herein, the term “isolated” in reference to solid state form oftrisodium valsartan:sacubitril of the present invention corresponds to asolid state form of trisodium valsartan:sacubitril that is physicallyseparated from the reaction mixture in which it is formed.

As used herein, unless stated otherwise, the XRPD measurements are takenusing copper Kα radiation wavelength 1.5418 Å.

As used herein, DSC measurements are obtained at a heating rate of 10°C./minute, under a nitrogen flow of 50 ml/min.

As used herein, solid state ¹³C NMR was carried out at 125 MHz at 0° C.,spinning rate 11 kHz.

As used herein, TGA analysis is carried out at a heating rate of 5° C.per minute to 250° C., preferably with a nitrogen flow of 20 ml/min.

As used herein, circularity refers to the ratio of the perimeter of acircle with the same area as the particle divided by the perimeter ofthe actual particle image. Circularity is preferably determined bymeasurement of the particles following sieving through a sieve having apore size of 300 μm. The particles are preferably measured followinganalysis of photographs of the particles at an appropriate magnification(e.g. 2.5 to 5.0 times magnification). More particularly, the sample isanalyzed using Morphologi G3 instrumentation. The collected data can beprocessed using image analysis. Circularity is a ratio of the perimeterof a circle with the same area as the particle divided by the perimeterof the actual particle image.

A thing, e.g., a reaction mixture, may be characterized herein as beingat, or allowed to come to “room temperature” or “ambient temperature”,often abbreviated as “RT.” This means that the temperature of the thingis close to, or the same as, that of the space, e.g., the room or fumehood, in which the thing is located. Typically, room temperature is fromabout 20° C. to about 30° C., or about 22° C. to about 27° C., or about25° C.

The amount of solvent employed in a chemical process, e.g., a reactionor a crystallization, may be referred to herein as a number of “volumes”or “vol” or “V.” For example, a material may be referred to as beingsuspended in 10 volumes (or 10 vol or 10V) of a solvent. In thiscontext, this expression would be understood to mean milliliters of thesolvent per gram of the material being suspended, such that suspending a5 grams of a material in 10 volumes of a solvent means that the solventis used in an amount of 10 milliliters of the solvent per gram of thematerial that is being suspended or, in this example, 50 mL of thesolvent. In another context, the term “v/v” may be used to indicate thenumber of volumes of a solvent that are added to a liquid mixture basedon the volume of that mixture. For example, adding solvent X (1.5 v/v)to a 100 ml reaction mixture would indicate that 150 mL of solvent X wasadded.

A process or step may be referred to herein as being carried out“overnight.” This refers to a time interval, e.g., for the process orstep, that spans the time during the night, when that process or stepmay not be actively observed. This time interval is from about 8 toabout 20 hours, or about 10-18 hours, typically about 16 hours.

As used herein, the term “reduced pressure” refers to a pressure that isless than atmospheric pressure. For example, reduced pressure is about10 mbar to about 100 mbar.

As used herein dissipation energy is calculated using Visimix softwareaccording to the reactor geometry (e.g. reactor diameter), impellerdiameter and impeller type, baffle type and width, clearance of baffleand impeller from bottom of reactor, liquid height and density of thesolution or suspension, which can be readily determined by a chemicalengineer.

As used herein, and unless indicated otherwise, the terms “wetcrystalline form” or “wet form” refer to a polymorph that was not driedusing any conventional techniques to remove residual solvent. Examplesfor such conventional techniques can be, but not limited to,evaporation, vacuum drying, oven drying, drying under nitrogen flow,etc.

As used herein, and unless indicated otherwise, the terms “drycrystalline form” or “dry form” refer to a polymorph that was driedusing any conventional techniques to remove residual solvent. Examplesfor such conventional techniques can be, but not limited to,evaporation, vacuum drying, oven drying, drying under nitrogen flow,etc.

In one embodiment, crystalline form II of trisodium valsartan:sacubitrilmay be characterized by data selected from one or more of the following:an X-ray powder diffraction pattern having peaks at 5.8, 7.3, 12.9,15.9, 16.5 and 18.6 degrees two theta±0.2 degrees two theta; and/or anX-ray powder diffraction pattern having peaks at: 7.3, 16.5, 9.4, 10.9and 14.7 two theta±0.2 degrees two theta; and/or X-ray powderdiffraction d-spacings at: 20.341, 15.261, 12.068, 9.397, 8.826, 8.092,6.863, 6.024, 5.583, 5.353 and 4.773 Å±0.1 Å; and/or a solid state ¹³CNMR spectrum having peaks at 176.8, 161.9, 141.1, 139.5, 138.6, 137.2,129.3, 128.7, 126.3, 124.9, 64.2, 60.6, 47.5, 46.1, 40.1, 39.0, 38.1,34.3, 32.7, 29.8, 28.2, 22.4, 20.2, 17.8, 16.5, 13.7, 11.7 ppm±0.2 ppm.

In one embodiment, the present invention comprises crystalline trisodiumvalsartan:sacubitril, designated form II, characterized by data selectedfrom one or more of the following: X-ray powder diffraction patternhaving peaks at 5.8, 7.3, 12.9, 15.9, 16.5 and 18.6 degrees twotheta±0.2 degrees two theta; an X-ray powder diffraction pattern asdepicted in FIG. 1; a solid-state ¹³C NMR spectrum as depicted in FIG.5; and combinations of this data.

Crystalline form II of trisodium valsartan:sacubitril can be furthercharacterized by: the X-ray powder diffraction pattern having peaks at5.8, 7.3, 12.9, 15.9, 16.5 and 18.6 degrees two theta±0.2 degrees twotheta and also having any one, any two, any three or more additionalpeaks selected from: 4.3, 9.4, 10.0, 10.9 and 14.7 two theta±0.2 degreestwo theta; an FTIR spectrum as depicted in FIG. 6; and combinations ofthis data.

Alternatively, crystalline form II of trisodium valsartan:sacubitril maybe characterized by data selected from one or more of the following:X-ray powder diffraction pattern having peaks at: 7.3, 16.5, 9.4, 10.9and 14.7 two theta±0.2 degrees two theta; an X-ray powder diffractionpattern as depicted in FIG. 1; a solid-state ¹³C NMR spectrum asdepicted in FIG. 5; and combinations of this data. In an alternativeembodiment, crystalline form II of trisodium valsartan:sacubitril may becharacterized by an X-ray powder diffraction pattern substantially asdepicted in FIG. 14, and/or a solid-state ¹³C NMR spectrum as depictedin FIG. 5.

Crystalline form II of trisodium valsartan:sacubitril can be furthercharacterized by the X-ray powder diffraction pattern having peaks at7.3, 16.5, 9.4, 10.9 and 14.7 two theta±0.2 degrees two theta and alsohaving any one, any two, any three or more additional peaks selectedfrom: 4.3, 5.8, 10.0, 12.9, 15.9 and 18.6 two theta±0.2 degrees twotheta; an FTIR spectrum as depicted in FIG. 6; and combinations of thisdata.

Crystalline Form II of trisodium valsartan:sacubitril may becharacterized by each of the above characteristics alone and/or by allpossible combinations.

The full PXRD peak list of crystalline trisodium valsartan:sacubitrilform II is specified in Table 1 (peak positions were corrected usingsilicon standard peak value at 28.45 deg. two theta). A skilled personwill be able to identify the peaks that are characteristic for Form II(i.e., not necessarily the most intense peaks) from such a list and,optionally the accompanying PXRD pattern. It is also well known in theart that the intensity of the peaks may exhibit a certain variation;depending on the specific circumstances of the measurement (instrumentsused, possible orientation effects, etc.). Accordingly, the intensity isoften not a useful parameter to unequivocally define a given crystallineform. Typically, a combination of 4-6 peaks that are unique to thisspecific form are sufficient to define a crystalline form. For example,crystalline form II can be characterized by peaks at 5.8, 7.3, 12.9,15.9, 16.5 and 18.6 degrees two theta±0.2 degrees two theta, andoptionally characterized by any one, any two, any three or moreadditional peaks selected from: 4.3, 9.4, 10.0, 10.9 and 14.7 twotheta±0.2 degrees two theta. It will be appreciated that it may benecessary to use further peaks from the PXRD peak list in order toproperly distinguish said crystalline form from other crystalline forms,e.g. crystalline forms that were yet unknown to the inventors at thefiling date of this application. It is contemplated that any peak orcombination of peaks from said peak list may be used to further definethe crystalline form. Accordingly, Form II may optionally be furtherdefined by one, two, three, four, five, or more than five additionalpeaks from the peak list presented in Table 1. In addition oralternatively, the crystalline Form II may also be further defined bythe absence of any peaks (defined as relative intensity I/Io of lessthan 1%) between any of two neighboring peaks in the peak list. Theassociated PXRD pattern (see FIG. 1) may assist in identifying suchcharacteristic areas where no peak is present for form II.

Form II of the present invention can be further characterized bydifferential scanning calorimetry (DSC) as shown in FIG. 2 and/orfurther characterized by a solid state ¹³C NMR as depicted in FIG. 5.

Form II may in certain embodiments be characterized, alternatively or inaddition, by a characteristic d-spacing as shown in Table 2. Thed-spacing values are calculated from two-theta values using HighScoresoftware (v. 2.2 a), based on Bragg's law.

Deviation is 0.1 Å.

In some embodiments, crystalline Form II of the present invention is ahydrate. Preferably the crystalline form may contain from 5.2 to 5.7 wt% water (e.g. as determined by TGA)(i.e., water which is part of thecrystal structure).

In some embodiments of the present invention, the crystalline Form II asdefined according to any aspect or embodiment described herein, may beprovided in a particular morphology. In particular the crystalline FormII may comprise agglomerates having spherical morphology. Theagglomerates themselves comprise primary particles. In preferredembodiments, the crystalline Form II comprises: at least 50%, at least60%, at least 70%, at least 80%, or at least 90% (preferably on a volumebasis) of agglomerates having spherical morphology. The degree ofspherical morphology can be further defined by circularity. Circularityis the ratio of the perimeter of a circle with the same area as theparticle divided by the perimeter of the actual particle image, and canbe readily determined by image analysis of the particles. Image analysismay be carried out according to the procedure described below.Preferably, crystalline Form II may comprise agglomerates havingspherical morphology such that at least 50% of the particles on a volumebasis (v 0.5) is: greater than or equal to about 0.85, about 0.86 to 1,about 0.88 to about 0.98, about 0.90 to about 0.96, about 0.92 to about0.96. The primary particles forming the aggregates may have a differentmorphology, for example, plate-like morphology. Crystalline Form IIcomprising agglomerates having spherical morphology as described hereinprovides advantageous processing characteristics and/or stability due toparticles having uniform morphology.

It has been found that agitation of the mixture during thecrystallization of the trisodium valsartan:sacubitril Form II from asolution during a crystallization procedure (for example during, orafter—preferably after—a cooling step) can affect the morphology of theproduct. In particular, it has been found that crystalline Form IIcomprising agglomerates having spherical morphology as defined hereincan be prepared by controlling the agitation (stirring). Particularly,the agitation is conducted at a dissipation energy of ≤2.0 W/kg, morepreferably at a dissipation energy of 0.2 to 2.0 W/kg, more preferablyat a dissipation energy of 0.5 to 1.5 W/kg, and most preferably at adissipation energy of 0.5 to 1 W/kg. The agitation can be carried outfor: about 0.1 to about 5 hours, about 0.25 to about 4 hours, or about 1to about 3 hours. Preferably, the dissipation energy is set to 1.7 orlower after crystallization occurs. Preferably the agitation is carriedout at a temperature of 45-55° C.

Crystalline Form II of the present invention and pharmaceuticalcompositions containing crystalline Form II can be prepared according tothe processes described herein. Preferably, the processes as describedherein are carried out such that the crystallization of the Form II isdone in the presence of water, for example either water added during thereaction or residual water in the solvents or reactants or water presentin the starting materials (e.g. such as LCZ696 which is a hydrated form,valsartan disodium hydrate—e.g. valsartan disodium trihydrate) or in thepresence of atmospheric water, or by a step of exposure to high relativehumidity.

A process for preparing a crystalline form II of trisodiumvalsartan:sacubitril comprising: (i) combining trisodiumvalsartan:sacubitril (preferably in hydrate form, e.g. LCZ696) with asolvent and heating (preferably to a temperature of about 80° C. toabout 150° C., about 90° C. to about 130° C.) to form a solution,preferably wherein the solvent comprises an aromatic solvent, preferablytoluene and/or methyl benzoate; (ii) cooling the solution (preferably toa temperature of about 4-28° C., preferably about 5 to about 25° C. andmore preferably about 5 to about 20° C.) to obtain a mixture, and (iii)isolating the crystalline form from the mixture, preferably wherein thetrisodium valsartan sacubitril is a hydrate form. Alternativelycrystalline form II of trisodium valsartan:sacubitril comprising can beprepared by a process comprising: (i) combining disodium valsartan(preferably in hydrate form, and more preferably a trihydrate) andsacubitril sodium with a solvent (preferably wherein the solvent is orcomprises toluene) to form a solution, (ii) cooling and/or removing atleast a portion of the solvent to obtain a mixture, and (iii) isolatingthe crystalline form from the mixture. In these processes, step (iii)can comprise filtering the mixture from step (ii), and exposing theresulting solid to a relative humidity of about 40 to 80%, preferably 50to 70% and more preferably about 60%. Alternatively, in the processcombining disodium valsartan (preferably in hydrate form, and morepreferably a trihydrate) and sacubitril sodium the isolating step cancomprise filtering the mixture obtained in step (ii), slurrying thesolid in a solvent comprising a C6-C10 alkane, preferably n-heptane, andisolating the crystalline form.

In another aspect of the present invention, there is provided a processfor preparing a crystalline form II of trisodium valsartan:sacubitrilcomprising: (i) providing a solution of sacubitril in a solvent,preferably wherein the solvent is water immiscible, more preferablywherein the solvent comprises ethyl acetate and/or toluene, and mostpreferably wherein the solvent is ethyl acetate or toluene, (ii) addingvalsartan acid and a sodium base, preferably sodium carbonate or sodiumhydroxide, and more preferably in a molar equivalent of about 2.8 toabout 3.2 moles of sodium per mole of valsartan or sacubitril, to thesacubitril solution, and (iii) isolating the crystalline form.Optionally, after adding the valsartan acid and sodium base and prior toisolating the crystalline form, the following steps can be carried out(ii-a) optionally removing the solvent, (ii-b) optionally adding tolueneand water to form a mixture, (ii-c) optionally heating the mixture, and(ii-d) cooling the mixture. Preferably, the process comprises the stepsof: (i) providing a solution of sacubitril in a solvent (preferablywherein the solvent is water immiscible and more preferably wherein thesolvent comprises ethyl acetate and/or toluene, and most preferablywherein the solvent is ethyl acetate or toluene), (ii) adding valsartanacid and a sodium base (preferably sodium carbonate or sodium hydroxide,and more preferably in a molar equivalent of about 2.8 to about 3.2moles of sodium per mole of valsartan or sacubitril), to the sacubitrilsolution, (ii-a) optionally removing the solvent, (ii-b) optionallyadding toluene and water to form a mixture, (ii-c) optionally heatingthe mixture, (vii-d cooling the mixture, and (iii) isolating thecrystalline form from the mixture. Step (iii) can comprise filtering themixture from step (ii-b) or (ii-d), suspending the resulting solid in asolvent (preferably wherein the solvent is or comprises a C6-C10 alkane,more preferably heptane), and filtering. In a preferred embodiment, thesolution of sacubitril in a solvent is prepared by combining an alkalior alkali earth metal salt of sacubitril, preferably in the form of ahydrate, in the solvent (preferably wherein the solvent comprises ethylacetate or toluene), and acidifying with an aqueous mineral acid,preferably hydrochloric acid, and removing the aqueous layer. Preferablysacubitril hemicalcium salt is used, and the crystallization of form IIis conducted in the presence of water. The use of water in an amount ofabout 94 to about 138 ml of water (more preferably about 120 to about130 ml of water) water per kg of sacubitril hemicalcium salt ispreferred. The amount of water is calculated with respect to sacubitrilhemicalcium in anhydrous form. The preferred amount of water present ispreferably calculated depending on the assayed amount of water presentin the reaction. Thus, preferably, the amount of water already presentin the reaction is determined, and is subtracted from the amount of 94to about 138 ml (per kg of sacubitril hemicalcium), and only thedifference to make the quantity up to about 94 to about 138 ml (or 120to 130 ml) per kg of sacubitril hemicalcium salt is added.

In another aspect, the present invention provides a process forpreparing a crystalline form II of trisodium valsartan:sacubitrilcomprising: (i) combining valsartan acid and sacubitril acid with anorganic solvent, preferably wherein the solvent comprises ethyl acetate,(ii) adding aqueous sodium hydroxide, preferably in a molar equivalentamount of 3.0-3.1 per mole of valsartan acid or relative to sacubitrilacid, to form a mixture, and (iii) isolating the crystalline form.Preferably, after adding the aqueous sodium hydroxide, and prior toisolating the crystalline form, the following steps are carried out:(ii-a) optionally removing a portion of the solvent, (ii-b) adding anorganic solvent, preferably comprising toluene to the mixture, (ii-c)optionally concentrating the mixture, (ii-d) optionally repeating step(ii-b), (ii-e) heating the mixture, (ii-f) cooling the mixture, and(ii-g) filtering the resulting solid and subjecting the solid to arelative humidity of about 40 to 80%, preferably 50 to 70% and morepreferably about 60%. In a preferred embodiment, the process comprisesthe steps of (i) combining valsartan acid and sacubitril acid with anorganic solvent, preferably wherein the solvent comprises ethyl acetate;(ii) adding aqueous sodium hydroxide, preferably in a molar equivalentamount of 3.0-3.1 per mole of valsartan acid or relative to sacubitrilacid, to form a mixture; (ii-a) optionally removing a portion of thesolvent; (ii-b) adding an organic solvent, preferably comprising tolueneto the mixture; (ii-c) optionally concentrating the mixture, (ii-d)optionally repeating step (ii-b); (ii-e) heating the mixture; (ii-f)cooling the mixture; (ii-g) filtering the resulting solid and subjectingthe solid to a relative humidity of about 40 to 80%, preferably 50 to70% and more preferably about 60%; and (iii) isolating the crystallineform from the mixture.

The crystallization processes of the present invention canadvantageously be used to prepare crystalline form II of trisodiumvalsartan:sacubitril comprising aggregates having spherical morphologyas described in any embodiment of the present invention disclosedherein. The applicant has found that the morphology of the aggregatescan be controlled by agitating (stirring) the mixture during and/orafter (preferably after) cooling provided that the agitation isconducted at a dissipation energy of ≤2.0 W/kg. Preferably, theagitation or stirring is carried out at a dissipation energy of 0.2 to2.0 W/kg, more preferably at a dissipation energy of 0.5 to 1.5 W/kg,and most preferably at a dissipation energy of 0.5 to 1 W/kg. Preferablythe agitation is carried out for a sufficient time to enable toproduction of aggregates having spherical morphology. For example, themixture can be agitated for: about 0.1 to about 5 hours, about 0.25 toabout 4 hours, or about 1 to about 3 hours.

In accordance with another aspect of the present invention, there isprovided a process for preparing a crystalline form II of trisodiumvalsartan:sacubitril comprising homogenizing (e.g. grinding in a mortar)a mixture of valsartan acid, sacubitril sodium and sodium hydroxide,preferably in a molar equivalent amount of 2.0-2.1 per mole of valsartanacid, in a solvent to form a mixture, preferably wherein the solventcomprises toluene. The homogenizing is preferably conducted in air, i.e.in the presence of atmospheric water.

Another aspect of the invention provides a process for preparing acrystalline form II of trisodium valsartan:sacubitril comprisingsuspending a mixture of valsartan disodium (preferably in hydrated form)and sacubitril sodium in a solvent (preferably wherein the solvent is,or comprises, toluene and/or 2-methyl tetrahydrofuran). The suspendingmay be carried out for a sufficient time to form crystalline Form II,for example, the suspending may be carried out for about 0.5 to about 12hours, more preferably for about 1 to about 8 hours, and particularlyfor about 2 to about 5 hours.

Also provided in another aspect of the present invention, is a processfor preparing crystalline form II of trisodium valsartan:sacubitrilcomprising contacting trisodium valsartan:sacubitril, preferably inamorphous form with a solvent comprising at least one of t-butyl methylether, 2-methyl tetrahydrofuran, or an aromatic solvent, preferablytoluene or methyl benzoate, wherein the contacting is preferably carriedout at room temperature. In a preferred embodiment, the contactingcomprises exposing the amorphous trisodium valsartan:sacubitril tovapours of the solvent, preferably for about 2 to about 14 days, morepreferably for about 3-10 days, and particularly for about 5-8 days.Alternatively, the contacting comprises slurrying amorphous trisodiumvalsartan:sacubitril in the solvent, for a sufficient time to formcrystalline Form II. Preferably the slurrying is carried out for about0.5 to about 12 hours, more preferably for about 2 to about 8 hours, andparticularly for about 2 to about 6 hours, and optionally isolating thecrystalline form.

In a further aspect of the present invention, there is provided aprocess for preparing crystalline trisodium valsartan:sacubitril form IIin a solvent comprising combining trisodium valsartan:sacubitril(preferably in hydrated form, such as LCZ696) with an aromatic solvent(preferably wherein the aromatic solvent is selected from chlorobenzene,fluorobenzene, m-xylene, o-xylene, p-xylene, anisole and methylbenzoate, and most preferably methyl benzoate), heating the mixture toform a solution, cooling the solution, and optionally isolating the formII. Prior to isolating the form II, the cooled solution is allowed toevaporate.

The above crystalline Form II of trisodium valsartan:sacubitril may beobtained either as a wet form, or a dry form.

In any of the aforementioned processes, the form II may be isolated anddried. The drying can optionally be carried out under reduced pressure,and optionally with heating, or the form II may be allowed.

The present invention further comprises a process as defined above,which further comprises combining the crystalline form of trisodiumvalsartan:sacubitril with at least one pharmaceutically acceptableexcipient to form a pharmaceutical composition.

The present invention further encompasses a crystalline form oftrisodium valsartan:sacubitril obtainable or obtained by any process asdefined in any embodiment or aspect described herein.

Crystalline form II trisodium valsartan:sacubitril according to anyaspect of the present invention or crystalline form II trisodiumvalsartan obtainable or obtained by the processes as described in anyaspect or embodiment disclosed herein may be combined with at least onepharmaceutically acceptable excipient to form a pharmaceuticalcomposition.

The invention further comprises crystalline trisodiumvalsartan:sacubitril according to present invention or prepared by theprocesses described herein for use as a medicament, preferably for thetreatment of hypertension and heart failure.

The above described solid state form can be used to prepare 1) othersolid state forms of trisodium valsartan:sacubitril; or 2) solid stateforms of valsartan:sacubitril; or 3) other salts of valsartan:sacubitriland their solid state forms. The present invention encompasses a processfor preparing other salts of valsartan:sacubitril or solid state formsthereof. The process comprises preparing form II of trisodiumvalsartan:sacubitril by the processes of the present invention, andconverting it to said other valsartan:sacubitril salt. The conversioncan be done, for example, by a process comprising acidifying the abovedescribed form II of trisodium valsartan:sacubitril, and reacting theobtained valsartan:sacubitril acid with an appropriate base, to obtainthe corresponding salt. Alternatively, the conversion can be done bysalt switching, i.e., reacting the trisodium valsartan:sacubitril, witha base having a pK_(a) which is higher than the pK_(a) of the base oftrisodium valsartan:sacubitril salt.

The above described solid state form of trisodium valsartan:sacubitrilcan be used to prepare chemically pure valsartan:sacubitril or saltsthereof. In certain embodiments, the present invention encompasses theabove described solid state form of trisodium valsartan:sacubitril foruse in the chemical purification of valsartan:sacubitril and saltsthereof.

The present invention further encompasses a process for chemicalpurification of trisodium valsartan:sacubitril. The process comprisescrystallizing form II of trisodium valsartan, preferably by the processof the present invention. In certain embodiments, the present inventioncomprises a process for chemical purification of trisodiumvalsartan:sacubitril comprising crystallizing trisodiumvalsartan:sacubitril from toluene.

The above described solid state forms of trisodium valsartan:sacubitrilcan be used to prepare pharmaceutical compositions and formulations. Incertain embodiments, the present invention comprises the above describedsolid state forms of trisodium valsartan:sacubitril for use in thepreparation of pharmaceutical compositions and formulations.

The present invention comprises pharmaceutical compositions andformulations comprising trisodium of valsartan:sacubitril of the presentinvention. Typically, the pharmaceutical composition is a solidcomposition and the trisodium valsartan:sacubitril retains its solidstate form.

The pharmaceutical compositions can be prepared by a process comprisingcombining the solid state form of trisodium valsartan:sacubitril of thepresent invention with at least one pharmaceutically acceptableexcipient.

The above solid state form of trisodium valsartan:sacubitril and/orpharmaceutical compositions of the present invention can also be used asa medicament.

The present invention further encompasses 1) the use of theabove-described solid state form of trisodium valsartan:sacubitril inthe manufacture of a pharmaceutical composition, and 2) a method oftreating a subject suffering from hypertension, or otherwise in need ofthe treatment, comprising administration of an effective amount of apharmaceutical composition comprising the above crystalline form oftrisodium valsartan:sacubitril described herein to a person in need ofthe treatment.

The present invention further provides a method of treating a subjectsuffering from hypertension or heart failure, comprising administrationof an effective amount of a pharmaceutical composition comprising acrystalline form II of trisodium valsartan:sacubitril as defined in anyaspect or embodiment disclosure herein, to a subject in need thereof.

Another aspect of the present invention provides a process for preparinga crystalline form of trisodium valsartan:sacubitril (preferably inhydrated form), wherein the crystalline form is characterized by dataselected from: (i) an X-ray powder diffraction pattern having peaks at4.2, 5.0, 6.5 and 12.6 degrees two theta±0.2 degrees two theta; andoptionally, one, two three or four additional peaks at 6.2 13.7, 14.9and 15.4 degrees two theta±0.2 degrees two theta; or (ii) an X-raypowder diffraction pattern having peaks at 4.2, 5.0, 6.5 and 12.6degrees two theta±0.2 degrees two theta; and additional peaks at 6.213.7, 14.9 and 15.4 degrees two theta±0.2 degrees two theta; or (iii) anX-ray powder diffraction pattern substantially as depicted in FIG. 12,wherein the process comprises crystallising trisodiumvalsartan:sacubitril (preferably in hydrated form) from a solventcomprising acetonitrile, acetone, ethyl acetate or isopropyl acetate, ora combination thereof. Preferably, the process comprises: suspendingvalsartan disodium trihydrate and sacubitril sodium in a solventcomprising acetonitrile, acetone, ethyl acetate or isopropyl acetate,optionally with stirring, and (b) optionally isolating the crystallineform. The solvent in step (a) is preferably acetonitrile. Step (a) ispreferably carried out for a period of from about 1 to about 18 hours,preferably from about 1 to about 12 hours, more preferably from about 2to about 10 hours. Preferably, step (a) is carried out at a temperatureof about 15 to about 40° C., preferably about 20 to about 30° C.Preferably, step (b) comprises filtering the solid and optionally dryingthe product, wherein the drying is preferably conducted at a temperatureof about 15 to about 40° C., preferably about 20 to about 30° C. In afurther embodiment, the present invention encompasses a crystalline formobtainable or obtained by this process. The invention furtherencompasses a pharmaceutical composition comprising a crystalline formobtainable by this process. In another embodiment, the process furthercomprises combining the crystalline form with at least onepharmaceutically acceptable excipient to form a pharmaceuticalcomposition.

Having thus described the invention with reference to particularpreferred embodiments and illustrative examples, those in the art canappreciate modifications to the invention as described and illustratedthat do not depart from the spirit and scope of the invention asdisclosed in the specification. The Examples are set forth to aid inunderstanding the invention but are not intended to, and should not beconstrued to limit its scope in any way.

X-Ray Powder Diffraction Method:

After the sample was powdered in a mortar and pestle it was applieddirectly on a silicon plate holder. The X-ray powder diffraction patternwas measured with Philips X′Pert PRO X-ray powder diffractometer,equipped with Cu irradiation source=1.54184 Å ({acute over (Å)}ngström),X'Celerator (2.022° 2θ) detector. Scanning parameters: angle range: 3-40deg, step size 0.0167, time per step 37 s, continuous scan. Thedescribed peak positions were determined using silicon powder as aninternal standard in an admixture with the sample measured. Due tonumber rounding the position of a few peaks was corrected based on theSi position.

DSC method:

DSC analysis was performed on Q1000 MDSC (TA instruments) with heatingrate of 10° C./min, under nitrogen flow of 50 ml/min. A hermeticaluminium, closed pan with hole was used, and the sample mass was about1-5 mg.

¹³C NMR method:

Solid-state ¹³C NMR spectra were recorded with variable amplitude crosspolarization, magic angle spinning and high power proton decouplingusing a BRUKER Avance II+ spectrometer operating at 125 MHz andcontrolled temperature (0° C.). A probe using 4 mm o.d. zirconia rotorswas employed. The operation conditions were: contact time: 2 ms; recycledelay: 4 s; 1024 scans and spin rate of 11 kHz. Chemical shifts werereferenced via a replacement sample of glycine (carboxyl carbon chemicalshift assigned as 176.03 ppm relative to the signal oftetramethylsilane).

FTIR method:

1-2 mg of sample was triturated with 200-300 mg of dry potassium bromideand mixture was compressed into a pellet with pressure of 700 MPa. Thespectrum of the sample was recorded over the range from 4000 to 400cm⁻¹, with resolution 2 cm⁻¹ and 16 scans. For background spectrum airwas used (empty sample compartment). Analysis was done on Nicolet 6700.

SEM Method:

SEM micrographs were taken on Joel JSM-5800 scanning microscope at 20kV, WD 20-22, low current. Samples were sputtered with gold by EdwardsS150 sputter coater.

Circularity Method:

Sample was sieved through a sieve with pore size 300 μm. The sievedmaterial was dispersed on the glass surface at 0.5 bar and then imageswere taken at 2.5-5.0× magnification using Morphologi G3 (Malvern).Collected data was processed using image analysis. Circularity is aratio of the perimeter of a circle with the same area as the particledivided by the perimeter of the actual particle image.

TGA Method:

Thermogravimetric analysis was carried out on Mettler Toledo TG-DSC 1with the following method: 5 mg of sample was placed in closed aluminumpan with the pin hole. The sample was heated at a heating rate of 5° C.per minute to 250° C., and purging with nitrogen with flow 20 ml/min.

EXAMPLES Reference Example

The starting trisodium valsartan:sacubitril can be prepared according tothe examples of U.S. Pat. No. 8,877,938.

Example 1: Preparation of Crystalline Trisodium Valsartan:SacubitrilForm II

1.0 g of trisodium valsartan:sacubitril was suspended in toluene (20 ml)and heated to 105-110° C. (clear solution was formed). The clearsolution was stirred for 10 minutes at reflux temperature and was cooleddown to 20° C., stirred for 1 hour, cooled down to 5° C. and stirred for1 hour. The mixture was filtered off and the product was left at 20° C.for 20 hours. The crude material was further dried at 50° C. for 20hours under vacuum. The dried solid material was analyzed by XRPD-formII was obtained. The XRPD pattern of the obtained form is shown inFIG. 1. FIG. 2 shows the DSC of the obtained product.

Example 2: Preparation of Crystalline Trisodium Valsartan:SacubitrilForm II

30 mg trisodium Valsartan:sacubitril cocrystal was suspended in toluene(10 ml) and heated at 105-110° C. to obtain a clear solution. The clearsolution was cooled down to room temperature and left to evaporate for24 hours. The obtained product was analyzed by XRD and DSC-form II.

Example 3: Preparation of Amorphous Trisodium Valsartan:Sacubitril

5 g of trisodium valsartan:sacubitril cocrystal was dissolved in ethanolat 20° C. The solution was then spray dried at the following conditions:Pump 20%, Aspirator 100%, Tinl 100° C., Tout 50° C. The obtained whitepowder was analyzed by XRPD-amorphous. The XRPD pattern of the obtainedmaterial is shown in FIG. 3.

Example 4: Preparation of Crystalline Trisodium Valsartan:SacubitrilForm II

Valsartan acid (103 mg) and Sacubitril sodium (102 mg) were homogenizedin mortar then 2 ml of toluene and 21 mg of crude sodium hydroxide wereadded, reaction mixture was stirred for 5 minutes. Crude product wasanalyzed by XRPD and DSC-form II.

Example 5: Preparation of Crystalline Trisodium Valsartan:SacubitrilForm II

5.0 g of trisodium Valsartan-Sacubitril cocrystal (LCZ696) was suspendedin 20 ml of toluene and 0.04 ml of water. The mixture was heated to 110°C. and cooled down to room temperature. Reaction mixture was filtratedoff and wet sample was left at 60% RH at 20° C. for 20 hours. Sample wasdried 8 h at 40° C. and analyzed by XRPD and DSc-form II.

Example 6: Preparation of Crystalline Trisodium Valsartan:SacubitrilForm II

5.0 g of trisodium Valsartan-Sacubitril cocrystal (LCZ696) was suspendedin 20 ml of toluene and 0.1 ml of water. The mixture was heated at 110°C. and cooled down to room temperature. Reaction mixture was filtratedoff and wet sample was left at 60% RH at 20° C. for 20 hours. Sample wasdried 8 h at 40° C. and analyzed by XRPD and DSC-form II.

Example 7: Preparation of Crystalline Trisodium Valsartan:SacubitrilForm II

Valsartan di Sodium trihydrate (1.05 g) and Sacubitril Sodium (0.950 g)were dissolved in toluene (30 ml) by heating to 110° C. Reaction mixturewas stirred for 10 minutes at 110° C. and then cooled down. Reactionmixture was filtrated off, and wet sample was left at 60% RH for 20hours and then dried at 40° C. under reduced pressure for 8 hours.Product was analyzed by XRPD-solid form II.

Example 8: Preparation of Crystalline Trisodium Valsartan:SacubitrilForm II

Valsartan acid (1.0 g) and Sacubitril acid (0.940 g) were dissolved inethyl acetate and stirred for 15 minutes. Sodium hydroxide (25% aqueoussolution, 1.08 ml) and the obtained suspension was stirred for 2 hours.Reaction mixture was concentrated under reduced pressure at 40° C., andthen toluene (15 ml) was added. Reaction mixture was once againconcentrated under reduced pressure and 40° C. followed again by theaddition of toluene (15 ml). Reaction mixture was heated to 110° C.,stirred for 10 minutes, cooled down and filtrated off. The wet samplewas left at 60% RH for 96 hours and then dried at 40° C. under reducedpressure for 8 hours and analyzed by XRPD-form II.

Example 9: Preparation of Crystalline Trisodium Valsartan:SacubitrilForm II

Trisodium Valsartan:Sacubitril (LCZ696, 5 g) was suspended in toluene(20 ml) and heated to 105-110° C. Solution was stirred for 5 minutes atreflux temperature and cooled down to 20° C. Wet sample was dried at 50°C. for 24 hours under vacuum. White powder was obtained and analyzed byXRD-form II.

Example 10: Preparation of Crystalline Trisodium Valsartan:SacubitrilForm II

Amorphous trisodium salt of valsartan:sacubitril (100 mg) was exposed toatmosphere vapors of t-butyl methyl ether for 7 days at roomtemperature. The obtained product was analyzed by XRPD-form II.

Example 11: Preparation of Crystalline Trisodium Valsartan:SacubitrilForm II

Amorphous trisodium salt of valsartan:sacubitril (100 mg) was exposed toatmosphere vapor of toluene for 7 days at room temperature. The obtainedproduct was analyzed by XRPD-form II.

Example 12: Preparation of Crystalline Trisodium Valsartan:SacubitrilForm II

Amorphous trisodium salt of valsartan:sacubitril (500 mg) was suspendedin toluene (0.5 ml) and stirred for 4 hours. The obtained product wasanalyzed by XRPD-form II.

Example 13: Preparation of Crystalline Trisodium Valsartan:SacubitrilForm II

Amorphous trisodium salt of valsartan:sacubitril (500 mg) was suspendedof t-butyl methyl ether (0.5 ml) and stirred for 4 hours. The obtainedproduct was analyzed by XRPD-form II.

Example 14: Preparation of Crystalline Trisodium Valsartan:SacubitrilForm II

Valsartan disodium trihydrate (100 mg) and sacubitril sodium (100 mg)were suspended in toluene (2 ml) for 3 hours. The obtained product wasanalyzed by XRPD-form II.

Example 15: Preparation of Crystalline Trisodium Valsartan:SacubitrilForm II

Valsartan disodium trihydrate (100 mg) and sacubitril sodium (100 mg)were suspended in 2-methyl-tetrahydrofiuran (2 ml) for 3 hours. Theobtained product was analyzed by XRPD-form II.

Example 16: Preparation of Amorphous Trisodium Valsartan:Sacubitril

Equivalent amounts of valsartan disodium trihydrate and sacubitrilsodium in total mass of mixture (5.0 g) were dissolved in ethanol (96%,75 ml). Solution was spray dried with inlet temperature 100° C., pumprate 20% and aspiration rate 75%. Powder obtained by spray drying wascharacterized by XRPD and was found to be amorphous.

Example 17: Preparation of Amorphous Trisodium Valsartan:Sacubitril

Valsartan disodium trihydrate (8.0 g) and sacubitril sodium (7.24 g)were dissolved in toluene (230 ml) at reflux temperature. The solutionwas then cooled down from reflux to 20° C. with a cooling rate of 15°C./h. Precipitation occurred at 36° C. Upon reaching 20° C., toluene wasdecanted off and the wet product was suspended in n-heptane (616 ml) andagitated at 20-25° C. for 30 min. The suspension was filtered over aBüchner funnel under nitrogen and the wet product was dried at 40° C.under reduced pressure until constant mass was obtained. The obtainedproduct was analyzed by XRPD-Amorphous.

Example 18: Preparation of Crystalline Trisodium Valsartan:SacubitrilForm II

In a 31 jacketed glass reactor, valsartan disodium trihydrate (70.4 g)and sacubitril sodium (57.2 g) were dissolved in toluene (2410 ml) atreflux temperature. The solution was cooled down from reflux to 40° C.over 60 minutes. The obtained suspension was stirred at 40° C. for 5 hfollowed by cooling to 20° C. over 60 minutes. The suspension wasstirred for 15 h at 20° C., and then filtered over a Büchner funnelunder nitrogen. The wet product was suspended in n-heptane (2680 ml) andagitated at 20-25° C. for 30 min. The suspension was again filtered overa Büchner funnel under nitrogen and the wet product was dried at 40° C.under reduced pressure (20 mbars) until constant mass was obtained. Theobtained material was analyzed by XRPD (Form II-FIG. 14), SSNMR and FTIR(FIGS. 5 and 6, accordingly).

Example 19: Preparation of Crystalline Trisodium Valsartan:SacubitrilForm II

In a 11 jacketed glass reactor valsartan disodium trihydrate (24.00 g)and sacubitril sodium (19.50 g) were dissolved in toluene (875 ml) atreflux temperature. The solution was cooled down from reflux to 48° C.over 60 minutes. The suspension was stirred at 50° C. for 2 h at maximumdissipation energy of 0.7 W/kg followed by cooling to 20° C. over 35minutes. The suspension was stirred at maximum dissipation energy of 0.7W/kg for 1 h and then filtered over a Büchner funnel under nitrogen. Theproduct was washed twice with methyl tert-butyl ether (175 ml). anddried at 25° C. under reduced pressure over 5 h (20 mbars) untilconstant mass was obtained. The obtained spherical material (see FIG. 7)was analyzed by XRPD-Form II.

Example 20: Preparation of Crystalline Trisodium Valsartan:SacubitrilForm II

Sacubitril hemicalcium salt (5.00 g) was suspended in ethyl-acetate (210ml) at room temperature. HCl (2M, 28.5M) was added and the mixture wasagitated for 30 minutes. Layers were separated and the organic layer waswashed with water. Valsartan acid (4.95 g) and sodium carbonate (1.78gr) were added into the ethyl-acetate solution, heated to 40° C. andagitated for 60 min. The solvent was evaporated to dryness. 100 ml oftoluene was added to the residue and the solvent was evaporated todryness. Toluene (210 ml) was added to the residue and the mixture washeated to 80° C. Water (0.5 ml) was added and the mixture was cooleddown to 50° C. and stirred for 2 h followed by cooling to 20° C. Thesuspension was stirred for 1 h at 20° C. and then filtered over aBüchner funnel. The wet product was suspended in n-heptane (60 ml) andagitated at 20-25° C. for 30 min. The suspension was again filtered overa Büchner funnel. The product was washed with n-heptane (30 ml) anddried at 25° C. under reduced pressure (20 mbars) until constant masswas obtained. Material was analyzed by XRPD-Form II.

Example 21: Preparation of Sacubitril Sodium

In a 11 jacketed glass reactor, sacubitril hemicalcium salt (40 gr) wassuspended in ethyl acetate (402 ml) at room temperature. HCl (2M, 58 ml)was added over 60 minutes. The mixture was agitated until dissolutionand the layers were separated. The organic layer was washed with water(3*133 ml) and evaporated to dryness. The remaining residue wasdissolved in acetonitrile (741 ml) and NaOH (10M, 6.9 ml) was added intothe solution at room temperature. The suspension was stirred at 22° C.over 20 h. The suspension was filtered over a Büchner funnel undernitrogen and the product was washed with acetonitrile (1*200 ml). Thewet product was dried at 35° C. under reduced pressure until constantmass was obtained. Material was analyzed by XRPD (FIG. 8).

Example 22: Preparation of Valsartan Disodium Trihydrate

In a 31 jacketed glass reactor, valsartan acid (300 g) was dissolved inacetone (1200 ml) at room temperature. Sodium carbonate (73.5 gr) anddeionized water (60 ml) were added and heated up to reflux temperature.The mixture was agitated at reflux for 3 hours and afterwards cooled toroom temperature. Methyl tert-butyl ether (MTBE) (1200 ml) was added andthe mixture was stirred for 15 hours at 20° C. The suspension wasfiltered over a Büchner funnel and the wet product was washed with amixture of acetone:MTBE (1:1, 300 ml). The wet product was dried at 35°C. under reduced pressure (20 mbars) until constant mass was obtained.Material was analyzed by XRPD (FIG. 9).

Example 23: Bulk Density and Tan Density of Form II

Samples of Form II were analyzed in the range of 10-20 g. Whole amountmaterial was put in graduated cylinder. A graduated cylinder with thesample was attached to Erweka SVM tapped density tester and tapped with1250 strikes. Volume of the powder is measured. Bulk density is measuredas ratio between mass of sample (ms) and unsettled apparent volume (V0)of sample in graduated cylinder. Tap Density is measured as ratiobetween mass of sample (ms) and final tapped volume of sample (Vf).Compressibility index and Hausner ratio were calculated according toobtained results of bulk and tapped density. Form II according to thepresent invention has a Hausner ratio of 1.10-1.14, and acompressibility index of 10-12. The flow properties of Form II arecharacterized as good-excellent (according to Carr RL. Evaluating flowproperties of solids. Chem Eng 1965; 72:163-168).

Example 24: SEM of Form II

An SEM micrograph was taken on Joel JSM-5800 scanning microscope at 20kV, WD 20-22, low current. Samples were sputtered with gold by EdwardsS150 sputter coater (FIG. 7).

Example 25: Preparation of LCZ696 with Characteristic Peaks at 4.2, 5.0,6.5 and 12.6 Degrees 2-Theta±0.2 Degrees 2-Theta

Valsartan disodium trihydrate (100 mg) and sacubitril sodium (100 mg)was suspended in 2 ml of acetonitrile for 3 hours. The obtained productwas analyzed by XRPD (FIG. 12).

Example 26: Preparation of LCZ6% with Characteristic Peaks at 4.2, 5.0,6.5 and 12.6 Degrees 2-Theta±0.2 Degrees 2-Theta

In a 11 glass jacketed reactor, 24.00 g of valsartan disodium trihydrateand 19.50 g of sacubitril sodium were suspended in 435 ml ofacetonitrile. The mixture was agitated at 25° C. over 8 h. Thesuspension was filtered over a Büchner funnel and the wet cake waswashed twice with 174 ml portions of MTBE. The wet product was dried at25° C. under reduced pressure until constant mass was obtained. Theobtained yield was 88.7%. Material was analyzed by XRPD and was found tocorrespond to FIG. 12.

Example 27: Preparation of LCZ696 with Characteristic Peaks at 4.2, 5.0,6.5 and 12.6 Degrees 2-Theta±0.2 Degrees 2-Theta

Valsartan disodium trihydrate (100 mg) and sacubitril sodium (100 mg)was suspended in 2 ml of acetone for 3 hours. The obtained product wasanalyzed by XRPD.

Example 28: Preparation of LCZ696 with Characteristic Peaks at 4.2, 5.0,6.5 and 12.6 Degrees 2-Theta±0.2 Degrees 2-Theta

Valsartan disodium trihydrate (100 mg) and sacubitril sodium (100 mg)was suspended in 2 ml of ethyl acetate for 3 hours. The obtained productwas analyzed by XRPD.

Example 29: Preparation of LCZ696 with Characteristic Peaks at 4.2, 5.0,6.5 and 12.6 Degrees 2-Theta±0.2 Degrees 2-Theta

Valsartan disodium trihydrate (100 mg) and sacubitril sodium (100 mg)was suspended in 2 ml of i-propy acetate for 3 hours. The obtainedproduct was analyzed by XRPD.

Example 30: Preparation of Crystalline Trisodium Valsartan:SacubitrilForm II

50 mg Trisodium Valsartan:Sacubitril cocrystal (LCZ696) is suspended inmethyl benzoate (10 ml) and heated at 140-150° C. Solution was cooleddown to room temperature and left to evaporate for 24 hours. Obtainedproduct was analyzed by XRD and DSC.

Example 31: Preparation of Crystalline Trisodium Valsartan:SacubitrilForm

In a 61 jacketed glass reactor, 100.0 g of sacubitril hemicalcium saltwas suspended in 4150 ml of toluene at room temperature. 570 ml of 2MHCl was added and the mixture was agitated for 30 minutes. Layers wereseparated and the organic layer was washed once with 1000 ml of water.The mixture was heated to 40° C. 99.1 g of valsartan acid and 35.7 g ofsodium carbonate were added and the mixture agitated for 90 min. Themixture was heated to reflux and water was removed out of the mixture byazeotropic distillation. The mixture was cooled to 80° C. followed byaddition of 12.3 ml of water. The mixture was cooled down to 50° C. uponwhich precipitation occurred. The suspension was stirred at 50° C. for 3hrs followed by cooling to 20° C. After a 2 h period of agitation at 20°C., the suspension was filtered over a 5 L filter dryer. The wet productwas suspended in 1200 ml of n-heptane and agitated at 20-25° C. for 15min. The cake wash was filtered off and the cake was washed again with300 ml of n-heptane. The product was dried in the filter dryer at 40° C.and under reduced pressure until loss on drying result below 5.0%. 183.5g of dry product was obtained.

Example 32: Morphology

Using the above-described method for determining morphology, crystallineForm II according to the invention (e.g. as prepared according toExample 19) was found to have circularity (v0.5) of greater than 0.85,i.e. 50% or greater of the agglomerates have a circularity of greaterthan 0.85.

Example 33: Thermogravimetric Analysis

Using the above-described method for TGA, the water content of thecrystalline Form II of the present invention is in the range of 5.2 to5.7 wt % (FIG. 13).

Example 34: Stability

Crystalline Form II of trisodium valsartan:sacubitril was found to bechemically and polymorphically stable when stored for 8 weeks at 25°C./60% RH, or at 50° C.

Crystalline Form II of trisodium valsartan:sacubitril was further foundto be chemically and polymorphically stable when protected from moistureand stored under the following conditions:

-   -   25° C./60% RH    -   40° C./75% RH    -   50° C.    -   50° C./80% RH

Further aspects and embodiments of the present invention are provided inthe following numbered Paragraphs:

-   1. Crystalline form II of trisodium valsartan:sacubitril    characterized by data selected from one or more of the following:    -   (i) an X-ray powder diffraction pattern having peaks at 5.8,        7.3, 12.9, 15.9, 16.5 and 18.6 degrees two theta±0.2 degrees two        theta; and/or    -   (ii) an X-ray powder diffraction pattern having peaks at: 7.3,        16.5, 9.4, 10.9 and 14.7 two theta±0.2 degrees two theta; and/or    -   (iii) X-ray powder diffraction d-spacings at: 20.341, 15.261,        12.068, 9.397, 8.826, 8.092, 6.863, 6.024, 5.583, 5.353 and        4.773 Å±0.1 Å; and/or    -   (iv) a solid state ¹³C NMR spectrum having peaks at 176.8,        161.9, 141.1, 139.5, 138.6, 137.2, 129.3, 128.7, 126.3, 124.9,        64.2, 60.6, 47.5, 46.1, 40.1, 39.0, 38.1, 34.3, 32.7, 29.8,        28.2, 22.4, 20.2, 17.8, 16.5, 13.7, 11.7 ppm±0.2 ppm.-   2. A crystalline form II of trisodium valsartan:sacubitril according    to Paragraph 1 characterized by data selected from one or more of    the following:    -   (i) an X-ray powder diffraction pattern having peaks at 5.8,        7.3, 12.9, 15.9, 16.5 and 18.6 degrees two theta±0.2 degrees two        theta; and/or    -   (ii) an X-ray powder diffraction pattern having peaks at: 7.3,        16.5, 9.4, 10.9 and 14.7 two theta±0.2 degrees two theta.-   3. A crystalline form according to Paragraph 2, which is    characterized by an X-ray powder diffraction pattern having peaks at    5.8, 7.3, 12.9, 15.9, 16.5 and 18.6 degrees two theta±0.2 degrees    two theta and also having any one, any two, any three or more    additional peaks selected from: 4.3, 9.4, 10.0, 10.9 and 14.7 two    theta±0.2 degrees two theta.-   4. A crystalline form according to Paragraph 2, which is    characterized by the X-ray powder diffraction pattern having peaks    at 7.3, 16.5, 9.4, 10.9 and 14.7 two theta±0.2 degrees two theta and    also having any one, any two, any three or more additional peaks    selected from: 4.3, 5.8, 10.0, 12.9, 15.9 and 18.6 two theta±0.2    degrees two theta and optionally further characterized by an FTIP    spectrum as depicted in FIG. 6.-   5. A crystalline form according to Paragraph 1 or Paragraph 2, which    is characterized by the X-ray powder diffraction pattern having    peaks at 4.3, 5.8, 7.3, 9.4, 10.0, 10.9, 12.9, 14.7, 15.9, 16.5, and    18.6 two theta±0.2 degrees two theta±0.2 degrees two theta-   6. A crystalline form according to Paragraph 5, which is further    characterized by X-ray powder diffraction d-spacings at: 20.341,    15.261, 12.068, 9.397, 8.826, 8.092, 6.863, 6.024, 5.583, 5.353 and    4.773 Å±0.1 Å.-   7. A crystalline form according to any of Paragraphs 1, 2, 3 or 4,    further characterized by an X-ray powder diffraction pattern having    one, two, three, four five, or more than 5 additional peaks selected    from: 4.3, 5.0, 5.5, 5.8, 7.3, 8.5, 8.9, 9.4, 10.0, 10.9, 11.6,    12.9, 13.7, 13.9, 14.7, 14.8, 15.1, 15.3, 15.9, 16.5, 17.3, 17.6,    18.6, 19.1, 19.5, 20.3, 21.2, 21.9 and 23.1 degrees two theta±0.2    degrees two theta-   8. A crystalline form according to any of Paragraphs 1, 2, 3, 4, 5,    6 or 7, which is characterized by an X-ray powder diffraction    pattern having peaks at: 4.3, 5.0, 5.5, 5.8, 7.3, 8.5, 8.9, 9.4,    10.0, 10.9, 11.6, 12.9, 13.7, 13.9, 14.7, 14.8, 15.1, 15.3, 15.9,    16.5, 17.3, 17.6, 18.6, 19.1, 19.5, 20.3, 21.2, 21.9 and 23.1    degrees two theta±0.2 degrees two theta.-   9. A crystalline form according to Paragraph 8, which is further    characterized by the absence of any peak (defined as relative    intensity I/Io of less than 1%) between any of two neighboring    peaks.-   10. A crystalline form according to any of Paragraphs 1, 2, 3, 4, 5,    6, 7, 8 or 9, further characterized by an X-ray powder diffraction    pattern as depicted in FIG. 1 or FIG. 14 and/or a solid state ¹³C    NMR as depicted in FIG. 5.-   11. A crystalline form according to any of Paragraphs 1, 2, 3, 4, 5,    6, 7, 8, 9 or 10, further characterized by a DSC as depicted in FIG.    2.-   12. A crystalline form according to any of Paragraphs 2-11 further    characterized by a solid state ¹³C NMR spectrum having peaks at    176.8, 161.9, 141.1, 139.5, 138.6, 137.2, 129.3, 128.7, 126.3,    124.9, 64.2, 60.6, 47.5, 46.1, 40.1, 39.0, 38.1, 34.3, 32.7, 29.8,    28.2, 22.4, 20.2, 17.8, 16.5, 13.7, 11.7 ppm±0.2 ppm.-   13. A crystalline form according to any of Paragraphs 1, 2, 3, 4, 5,    6, 7, 8, 9, 10, 11 or 12, which is substantially free of any other    forms of trisodium valsartan:sacubitril.-   14. A crystalline form according to any of Paragraphs 1, 2, 3, 4, 5,    6, 7, 8, 9, 10, 11, 12 or 13, which contains: 20% (w/w) or less, 10%    (w/w) or less; or 5% (w/w) or less; or 2% (w/w) or less of    polymorphs, or of a specified polymorph of trisodium    valsartan:sacubitril.-   15. A crystalline form according to any of Paragraphs 1, 2, 3, 4, 5,    6, 7, 8, 9, 10, 11, 12, 13 or 14, which contains: from 2% to 20%    (w/w); from 5% to 20% (w/w); or from 5% to 10% (w/w) of one or more    solid state forms or one or more polymorphs of trisodium    valsartan:sacubitril which is/are different from the predominant    solid state of trisodium valsartan:sacubitril which is present.-   16. A crystalline form according to any of Paragraphs 1, 2, 3, 4, 5,    6, 7, 8, 9, 10, 11, 12, 13, 14 or 15, which is a hydrate, preferably    wherein the crystalline form contains from 5.2 to 5.7 wt % water.-   17. A crystalline form according to any of Paragraphs 1, 2, 3, 4, 5,    6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16, comprising agglomerates    having spherical morphology, preferably wherein: at least 50%, at    least 60%, at least 70%, at least 80% or at least 90% of the    agglomerates have spherical morphology, preferably wherein the    circularity of at least 50% (preferably: at least 60%, at least 70%,    at least 80% or at least 90%) of the particles on a volume basis is:    greater than or equal to about 0.85, about 0.86 to 1, about 0.88 to    about 0.98, about 0.90 to about 0.96, about 0.92 to about 0.96.-   18. A process for preparing a crystalline form II of trisodium    valsartan:sacubitril comprising:    -   (i) combining trisodium valsartan:sacubitril with a solvent and        heating to form a solution, preferably wherein the solvent        comprises an aromatic solvent, preferably toluene and/or methyl        benzoate    -   (ii) cooling the solution to obtain a mixture, and    -   (iii) isolating the crystalline form from the mixture,        preferably wherein the trisodium valsartan sacubitril is a        hydrate form.-   19. A process for preparing a crystalline form II of trisodium    valsartan:sacubitril comprising:    -   (i) combining disodium valsartan and sacubitril sodium with a        solvent to form a solution, preferably wherein the solvent        comprises toluene,    -   (ii) cooling and/or removing at least a portion of the solvent        to obtain a mixture, and (iii) isolating the crystalline form        from the mixture,    -   preferably wherein the disodium valsartan is a hydrate form.-   20. A process according to any of Paragraphs 18 or 19, wherein the    solution in step (i) is prepared by heating, preferably to a    temperature of about 80° C. to about 150° C., about 90° C. to about    130° C.-   21. A process according to any of Paragraphs 18, 19 or 20, wherein    step ii) comprises cooling to a temperature of about 4-28° C.,    preferably about 5 to about 25° C. and more preferably about 5 to    about 20° C.-   22. A process according to any of Paragraphs 18, 19, 20 or 21,    wherein step (iii) comprises filtering the mixture from step (ii),    and exposing the resulting solid to a relative humidity of about 40    to 80%, preferably 50 to 70% and more preferably about 60%.-   23. A process according to any of Paragraphs 19, 20 or 21, wherein    the disodium valsartan is in the form of a hydrate, preferably a    trihydrate.-   24. A process according to Paragraph 23, wherein step (iii)    comprises filtering the mixture obtained in step (ii), slurrying the    solid in a solvent comprising a C₆-C₁₀ alkane, preferably n-heptane,    and isolating the crystalline form.-   25. A process for preparing a crystalline form II of trisodium    valsartan:sacubitril comprising:    -   (i) providing a solution of sacubitril in a solvent, preferably        wherein the solvent is water immiscible, more preferably wherein        the solvent comprises ethyl acetate and/or toluene, and most        preferably wherein the solvent is ethyl acetate or toluene,    -   (ii) adding valsartan acid and a sodium base, preferably sodium        carbonate or sodium hydroxide, and more preferably in a molar        equivalent of about 2.8 to about 3.2 moles of sodium per mole of        valsartan or sacubitril, to the sacubitril solution, and    -   (iii) isolating the crystalline form.-   26. A process according to Paragraph 25, wherein after adding the    valsartan acid and sodium base and prior to isolating the    crystalline form, the following steps are carried out:    -   (ii-a) optionally removing the solvent,    -   (ii-b) optionally adding toluene and water to form a mixture,    -   (ii-c) optionally heating the mixture, and    -   (ii-d) cooling the mixture.-   27. A process according to Paragraph 25 or Paragraph 26, wherein    step (iii) comprises filtering the mixture from step (ii-b) or    (ii-d), suspending the resulting solid in a solvent, preferably    wherein the solvent comprises a C₆-C₀₀ alkane, preferably heptane,    and filtering.-   28. A process according to any of Paragraphs 25, 26 or 27, wherein    the solution of sacubitril in a solvent is prepared by combining an    alkali or alkali earth metal salt of sacubitril (preferably    sacubitril hemicalcium salt), optionally in the form of a hydrate,    in the solvent (preferably wherein the solvent comprises ethyl    acetate or toluene), and acidifying with an aqueous mineral acid,    preferably hydrochloric acid, and removing the aqueous layer.-   29. A process according to Paragraph 28, wherein crystallization of    form II is conducted in the presence of water, preferably wherein    water is present in an amount of about 94 to about 138 ml of water    per kg of sacubitril alkali or alkali earth metal salt (preferably    relative to sacubitril hemicalcium salt in anhydrous form), more    preferably about 120 to about 130 ml of water per kg of sacubitril    alkali or alkali earth metal salt (preferably sacubitril hemicalcium    salt).-   30. A process for preparing a crystalline form II of trisodium    valsartan:sacubitril comprising:    -   (i) combining valsartan acid and sacubitril acid with an organic        solvent, preferably wherein the solvent comprises ethyl acetate,    -   (ii) adding aqueous sodium hydroxide, preferably in a molar        equivalent amount of 3.0-3.1 per mole of valsartan acid or        relative to sacubitril acid, to form a mixture, and    -   (iii) isolating the crystalline form.-   31. A process according to Paragraph 30, wherein after adding the    aqueous sodium hydroxide, and prior to isolating the crystalline    form, the following steps are carried out:    -   (ii-a) optionally removing a portion of the solvent,    -   (ii-b) adding an organic solvent, preferably comprising toluene        to the mixture,    -   (ii-c) optionally concentrating the mixture,    -   (ii-d) optionally repeating step (ii-b),    -   (ii-e) heating the mixture,    -   (ii-f) cooling the mixture, and    -   (ii-g) filtering the resulting solid and subjecting the solid to        a relative humidity of about 40 to 80%, preferably 50 to 70% and        more preferably about 60%.-   32. A process according to any of Paragraphs 18, 19, 20, 21, 22, 23,    24, 25, 26, 27, 28, 29, 30 or 31, wherein during and/or after    (preferably after) the step of cooling the mixture, the mixture is    agitated, preferably wherein the agitation is at a dissipation    energy of ≤2.0 W/kg, more preferably at a dissipation energy of 0.2    to 2.0 W/kg, more preferably at a dissipation energy of 0.5 to 1.5    W/kg, and most preferably at a dissipation energy of 0.5 to 1.0    W/kg, preferably wherein the dissipation energy is set to a lower    value of 1.7 W/kg after crystallization occurs, wherein the    agitation is preferably carried out at a temperature of 45-55° C.-   33. A process according to Paragraph 32 wherein the mixture is    agitated for: about 0.1 to about 5 hours, about 0.25 to about 4    hours, or about 1 to about 3 hours.-   34. A process for preparing a crystalline form II of trisodium    valsartan:sacubitril comprising homogenizing a mixture of valsartan    acid, sacubitril sodium and sodium hydroxide, preferably in a molar    equivalent amount of 2.0-2.1 per mole of valsartan acid, in a    solvent to form a mixture, preferably wherein the solvent comprises    toluene.-   35. A process for preparing a crystalline form II of trisodium    valsartan:sacubitril comprising suspending a mixture of valsartan    disodium (preferably in hydrated form) and sacubitril sodium in a    solvent, preferably wherein the solvent comprises toluene and/or    2-methyl tetrahydrofuran.-   36. A process according to Paragraph 35, wherein the suspending is    carried out for about 0.5 to about 12 hours, more preferably for    about 1 to about 8 hours, and particularly for about 2 to about 5    hours.-   37. A process for preparing a crystalline form II of trisodium    valsartan:sacubitril comprising contacting trisodium    valsartan:sacubitril, preferably in amorphous form with a solvent    comprising at least one of t-butyl methyl ether, 2-methyl    tetrahydrofuran, or an aromatic solvent, preferably toluene or    methyl benzoate, wherein the contacting is preferably at room    temperature.-   38. A process according to Paragraph 37, wherein the contacting    comprises exposing the amorphous trisodium valsartan:sacubitril to    vapours of the solvent, preferably for about 2 to about 14 days,    more preferably for about 3-10 days, and particularly for about 5-8    days.-   39. A process according to Paragraph 37, wherein the contacting    comprises slurrying the amorphous trisodium valsartan:sacubitril in    the solvent, preferably for about 0.5 to about 12 hours, more    preferably for about 2 to about 8 hours, and particularly for about    2 to about 6 hours, and optionally isolating the crystalline form.-   40. A process for preparing crystalline trisodium    valsartan:sacubutril form II in a solvent comprising combining    trisodium valsartan: sacubril (preferably in hydrated form) with an    aromatic solvent, preferably wherein the aromatic solvent is    selected from chlorobenzene, fluorobenzene, m-xylene, o-xylene,    p-xylene, anisole and methyl benzoate, and most preferably methyl    benzoate, heating the mixture to form a solution, cooling the    solution, and optionally isolating the form II.-   41. A process according to Paragraph 40 wherein prior to isolating    the form II, the cooled solution is allowed to evaporate.-   42. A process according to any of Paragraphs 18, 19, 20, 21, 22, 23,    24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40    or 41, further comprising drying the crystalline form optionally    under reduced pressure and optionally with heating.-   43. A process according to any of Paragraphs 18, 19, 20, 21, 22, 23,    24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40,    41 or 42, further comprising combining the crystalline form with at    least one pharmaceutically acceptable excipient to form a    pharmaceutical composition.-   44. A crystalline form II of trisodium valsartan:sacubitril    obtainable by a process according to any of Paragraphs 18, 19, 20,    21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37,    38, 39, 40, 41 or 42.-   45. A crystalline form II of trisodium valsartan:sacubitril    according to Paragraph 44, which is defined according to any of    Paragraphs 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or    17.-   46. A crystalline form II according to any of Paragraphs 1, 2, 3, 4,    5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 44 or 45 for use as a    medicament.-   47. A crystalline form according to any of Paragraphs 1, 2, 3, 4, 5,    6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 44, 45 or 46, for use in    the treatment of hypertension and heart failure.-   48. Use of a crystalline form according to any of Paragraphs 1, 2,    3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 44 or 45, for    the preparation of other solid state forms of trisodium    valsartan:sacubitril, for the preparation of solid state forms of    valsartan:sacubitril, or for the preparation of other salts of    valsartan:sacubitril and their solid state forms,-   49. Use of a crystalline form according to any of Paragraphs 1, 2,    3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 44 or 45, for    the chemical purification of valsartan:sacubitril and salts thereof.-   50. Use according to Paragraph 49, wherein the chemical purification    comprises crystallizing form II of trisodium valsartan:sacubitril,    preferably comprising crystallizing trisodium valsartan:sacubitril    from toluene.-   51. Use of a crystalline form according to any of Paragraphs 1, 2,    3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 44 or 45, for    the preparation of pharmaceutical compositions and/or formulations    of valsartan:sacubitril.-   52. A pharmaceutical composition or formulation comprising a    crystalline form according to any of Paragraphs 1, 2, 3, 4, 5, 6, 7,    8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 44 or 45, preferably wherein    the pharmaceutical composition is a solid composition and the    trisodium valsartan:sacubitril retains its solid state form.-   53. A pharmaceutical composition or formulation comprising a    crystalline form according to any of Paragraphs 1, 2, 3, 4, 5, 6, 7,    8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 44 or 45 and a    pharmaceutically acceptable excipient.-   54. A process for preparing a pharmaceutical composition or    formulation according Paragraph 52 or 53, comprising combining a    crystalline form according to any of Paragraphs 1, 2, 3, 4, 5, 6, 7,    8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 44 or 45 with at least one    pharmaceutically acceptable excipient.-   55. A method of treating hypertension or heart failure, comprising    administration of an effective amount of a pharmaceutical    composition comprising a crystalline form of trisodium    valsartan:sacubitril according to any of Paragraphs 1, 2, 3, 4, 5,    6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 44 or 45 to a subject in    need thereof.-   56. A process for preparing a crystalline form of trisodium    valsartan:sacubitril (preferably in hydrated form), wherein the    crystalline form is characterized by data selected from:    -   (i) an X-ray powder diffraction pattern having peaks at 4.2,        5.0, 6.5 and 12.6 degrees two theta±0.2 degrees two theta; and        optionally, one, two three or four additional peaks at 6.2 13.7,        14.9 and 15.4 degrees two theta±0.2 degrees two theta; or    -   (ii) an X-ray powder diffraction pattern having peaks at 4.2,        5.0, 6.5 and 12.6 degrees two theta±0.2 degrees two theta; and        additional peaks at 6.2 13.7, 14.9 and 15.4 degrees two        theta±0.2 degrees two theta; or    -   (iii) an X-ray powder diffraction pattern substantially as        depicted in FIG. 12, wherein the process comprises crystallising        trisodium valsartan:sacubitril (preferably in hydrated form)        from a solvent comprising acetonitrile, acetone, ethyl acetate        or isopropyl acetate or a combination thereof.-   57. A process according to Paragraph 56, wherein the process    comprises:    -   (a) suspending valsartan disodium trihydrate and sacubitril        sodium in a solvent comprising acetonitrile, ethyl acetate, or        isopropyl acetate, optionally with stirring, and    -   (b) optionally isolating the crystalline form.-   58. A process according to Paragraph 56 or Paragraph 57, wherein the    solvent in step (a) is acetonitrile.-   59. A process according to any of Paragraphs 56, 57 or 58, wherein    step (a) is carried out for a period of from about 1 to about 18    hours, preferably from about 1 to about 12 hours, more preferably    from about 2 to about 10 hours.-   60. A process according to any of Paragraphs 56, 57, 58 or 59,    wherein step (a) is carried out at a temperature of about 15 to    about 40° C., preferably about 20 to about 30° C.-   61. A process according to any of Paragraphs 56, 57, 58, 59 or 60,    wherein step (b) comprises filtering the solid and optionally drying    the product, wherein the drying is preferably conducted at a    temperature of about 15 to about 40° C., preferably about 20 to    about 30° C.-   62. A process according to any of Paragraphs 56, 57, 58, 59, 60 or    61, further comprising combining the crystalline form with at least    one pharmaceutically acceptable excipient to form a pharmaceutical    composition.-   63. A crystalline form of trisodium valsartan:sacubitril in hydrate    form or a pharmaceutical composition thereof, obtainable by a    process according to any of Paragraphs 56, 57, 58, 59, 60, 61 or 62.

1. Crystalline form II of trisodium valsartan:sacubitril characterizedby an X-ray powder diffraction pattern having peaks at: 7.3, 9.4, and16.5 degrees two theta±0.2 degrees two theta and an absence of a peak at12.4 degrees two theta±0.2 degrees two theta; or an X-ray powderdiffraction pattern having peaks at: 5.8, 7.3, 12.9, 15.9, 16.5 and 18.6degrees two theta±0.2 degrees two theta and an absence of a peak at 12.4degrees two theta±0.2 degrees two theta.
 2. The crystalline form ofclaim 1, characterized by an X-ray powder diffraction pattern havingpeaks at: 7.3, 9.4, and 16.5 degrees two theta±0.2 degrees two theta andfurther characterized by an X-ray powder diffraction pattern having oneor more additional peaks selected from: 5.8, 10.9, 12.9, 14.7, 15.9, and18.6 degrees two theta±0.2 degrees two theta.
 3. The crystalline form ofclaim 1, characterized by an X-ray powder diffraction pattern havingpeaks at: 7.3, 9.4, and 16.5 degrees two theta±0.2 degrees two theta andfurther characterized by an X-ray powder diffraction pattern having oneor more additional peaks selected from: 4.3, 5.8, 10.0, 10.9, 12.9,14.7, 15.9, and 18.6 degrees two theta±0.2 degrees two theta.
 4. Thecrystalline form of claim 1, characterized by an X-ray powderdiffraction pattern having peaks at: 7.3, 9.4, and 16.5 degrees twotheta±0.2 degrees two theta and further characterized by an X-ray powderdiffraction pattern having one or more additional peaks selected from:4.3, 5.0, 5.5, 5.8, 8.5, 8.9, 10.0, 10.9, 11.6, 12.9, 13.7, 13.9, 14.7,14.8, 15.1, 15.3, 15.9, 17.3, 17.6, 18.6, 19.1, 19.5, 20.3, 21.2, 21.9and 23.1 degrees two theta±0.2 degrees two theta.
 5. The crystallineform of claim 1, characterized by an X-ray powder diffraction patternhaving peaks at: 5.8, 7.3, 12.9, 15.9, 16.5 and 18.6 degrees twotheta±0.2 degrees two theta and further characterized by an X-ray powderdiffraction pattern having one or more additional peaks selected from:4.3, 9.4, 10.0, 10.9 and 14.7 degrees two theta±0.2 degrees two theta.6. The crystalline form of claim 1, characterized by an X-ray powderdiffraction pattern having peaks at: 5.8, 7.3, 12.9, 15.9, 16.5 and 18.6degrees two theta±0.2 degrees two theta and further characterized by anX-ray powder diffraction pattern having one or more additional peaksselected from: 4.3, 5.0, 5.5, 8.5, 8.9, 9.4, 10.0, 10.9, 11.6, 13.7,13.9, 14.7, 14.8, 15.1, 15.3, 17.3, 17.6, 19.1, 19.5, 20.3, 21.2, 21.9and 23.1 degrees two theta±0.2 degrees two theta.
 7. The crystallineform of claim 1, which is a hydrate form.
 8. The crystalline form ofclaim 7, wherein the crystalline form contains from 5.2 to 5.7 wt %water.
 9. The crystalline form of claim 1, comprising agglomerateshaving spherical morphology, wherein at least 50% of the agglomerateshave spherical morphology.
 10. The crystalline form of claim 1, whichcontains less than 10% (w/w) of any other forms of trisodiumvalsartan:sacubitril that is different from crystalline form II.
 11. Thecrystalline form of claim 1, which contains 5% (w/w) or less of anyother forms of trisodium valsartan:sacubitril that is different fromcrystalline form II.
 12. The crystalline form of claim 1, which contains2% (w/w) or less of any other forms of trisodium valsartan:sacubitrilthat is different from crystalline form II.
 13. Crystalline form II oftrisodium valsartan:sacubitril characterized by an X-ray powderdiffraction pattern as depicted in FIG.
 1. 14. The crystalline form ofclaim 13, further characterized by a DSC as depicted in FIG.
 2. 15. Apharmaceutical composition or formulation comprising the crystallineform II of trisodium valsartan:sacubitril as defined in claim 1 and atleast one pharmaceutically acceptable excipient.
 16. A process forpreparing a pharmaceutical composition or formulation according claim 15comprising combining crystalline form II of trisodiumvalsartan:sacubitril with at least one pharmaceutically acceptableexcipient.
 17. A method of treating hypertension or heart failure in asubject in need thereof, the method comprising administering to thesubject a therapeutically effective amount of crystalline form II oftrisodium valsartan:sacubitril as defined in claim 1; or apharmaceutical formulation comprising the therapeutically amount ofcrystalline form II of trisodium valsartan:sacubitril as defined inclaim 1 and at least one pharmaceutically acceptable excipient.